Haczeyni Fahrettin, Wang Hans, Barn Vanessa, Mridha Auvro R, Yeh Matthew M, Haigh W Geoffrey, Ioannou George N, Choi Yun-Jung, McWherter Charles A, Teoh Narcissus C-H, Farrell Geoffrey C
Liver Research Group Australian National University Medical School at the Canberra Hospital Canberra ACT Australia.
Department of Pathology University of Washington Seattle WA.
Hepatol Commun. 2017 Jul 31;1(7):663-674. doi: 10.1002/hep4.1072. eCollection 2017 Sep.
Lipotoxicity associated with insulin resistance is central to nonalcoholic steatohepatitis (NASH) pathogenesis. To date, only weight loss fully reverses NASH pathology, but mixed peroxisome proliferator-activated receptor-alpha/delta (PPAR-α/δ) agonists show some efficacy. Seladelpar (MBX-8025), a selective PPAR-δ agonist, improves atherogenic dyslipidemia. We therefore used this agent to test whether selective PPAR-δ activation can reverse hepatic lipotoxicity and NASH in an obese, dyslipidemic, and diabetic mouse model. From weaning, female mutant () mice and wild-type littermates were fed an atherogenic diet for 16 weeks; groups (n = 8-12) were then randomized to receive MBX-8025 (10 mg/kg) or vehicle (1% methylcellulose) by gavage for 8 weeks. Despite minimally altering body weight, MBX-8025 normalized hyperglycemia, hyperinsulinemia, and glucose disposal in mice. Serum alanine aminotransferase ranged 300-600 U/L in vehicle-treated mice; MBX-8025 reduced alanine aminotransferase by 50%. In addition, MBX-8025 normalized serum lipids and hepatic levels of free cholesterol and other lipotoxic lipids that were increased in vehicle-treated versus wild-type mice. This abolished hepatocyte ballooning and apoptosis, substantially reduced steatosis and liver inflammation, and improved liver fibrosis. In vehicle-treated mice, the mean nonalcoholic fatty liver disease activity score was 6.9, indicating NASH; MBX-8025 reversed NASH in all mice (nonalcoholic fatty liver disease activity score 3.13). : Seladelpar improves insulin sensitivity and reverses dyslipidemia and hepatic storage of lipotoxic lipids to improve NASH pathology in atherogenic diet-fed obese diabetic mice. Selective PPAR-δ agonists act independently of weight reduction, but counter lipotoxicity related to insulin resistance, thereby providing a novel therapy for NASH. ( 2017;1:663-674).
与胰岛素抵抗相关的脂毒性是非酒精性脂肪性肝炎（NASH）发病机制的核心。迄今为止，只有体重减轻能完全逆转NASH病理，但混合的过氧化物酶体增殖物激活受体α/δ（PPAR-α/δ）激动剂显示出一定疗效。塞拉达帕（MBX-8025）是一种选择性PPAR-δ激动剂，可改善致动脉粥样硬化性血脂异常。因此，我们使用该药物来测试选择性PPAR-δ激活是否能在肥胖、血脂异常和糖尿病小鼠模型中逆转肝脏脂毒性和NASH。从断奶开始，雌性突变（）小鼠和野生型同窝小鼠喂食致动脉粥样硬化饮食16周；然后将各组（n = 8 - 12）随机分为通过灌胃接受MBX-8025（10 mg/kg）或赋形剂（1%甲基纤维素），持续8周。尽管对体重影响极小，但MBX-8025使小鼠的高血糖、高胰岛素血症和葡萄糖处置恢复正常。在接受赋形剂治疗的小鼠中，血清丙氨酸氨基转移酶范围为300 - 600 U/L；MBX-8025使丙氨酸氨基转移酶降低了50%。此外，MBX-8025使血清脂质以及肝脏中游离胆固醇和其他脂毒性脂质水平恢复正常，这些脂质在接受赋形剂治疗的小鼠与野生型小鼠相比有所增加。这消除了肝细胞气球样变和凋亡，大幅减少了脂肪变性和肝脏炎症，并改善了肝纤维化。在接受赋形剂治疗的小鼠中，平均非酒精性脂肪性肝病活动评分是6.9，表明存在NASH；MBX-8025使所有小鼠的NASH得到逆转（非酒精性脂肪性肝病活动评分3.13）。结论：塞拉达帕可改善胰岛素敏感性，逆转血脂异常和脂毒性脂质的肝脏蓄积，从而改善喂食致动脉粥样硬化饮食的肥胖糖尿病小鼠的NASH病理。选择性PPAR-δ激动剂独立于体重减轻发挥作用，但可对抗与胰岛素抵抗相关的脂毒性，从而为NASH提供一种新的治疗方法。（2017；1：663 - 674）
